| abstract |
Major depressive disorder (MDD) affects approximately 20 million adults in the United
States. The prevailing theory suggests that MDD results from imbalances in monoamines such as
serotonin, norepinephrine, and dopamine; however, many MDD patients do not respond to drugs
that target these systems, indicating that the neurochemical causes of MDD may be more diverse
than originally suspected. Ketamine, an NMDA receptor antagonist with hallucinogenic and
dissociative properties, has been suggested as a treatment for patients who do not respond to
typical antidepressants. As a method of inducing depression-like behavior in rodents, the chronic
variable stress (CVS) protocol consists of exposing rodents to frequent, non-painful,
unpredictable stressors over an extended period and has been shown to result in depression-like
behavior in tests like the forced swim test (FST) that responds well to typical antidepressants.
Although affective disorders are more common in females, this population is underrepresented in
both human and animal trials, indicating a need for more studies using female subjects. This
study investigates if CVS would increase immobility and decrease latency to immobility in the
FST, and if ketamine would prevent these changes.
Female Sprague Dawley rats were exposed to CVS for three weeks to induce a model of
depression, then depression-like behaviors were measured using the FST, anxiety-like behaviors
were measured using the open field test (OFT) and elevated zero maze (EZM), and blood
samples were collected to measure the stress hormone corticosterone. Ketamine (10 mg/kg) or
saline was then administered via i.p. injection weekly for three weeks, and the FST was
administered multiple times during the same period. After three weekly injections of ketamine,
the OFT, EZM, and blood draws were repeated. Exposure to CVS had no effect on time spent
immobile in the FST at all time points, conversely to what was expected. There was also a
significant main effect of ketamine, but not CVS, in reducing the latency to immobility in the
FST. There was an effect of CVS in the OFT, but not the EZM; however, a comparison of
behavior in both behavioral tests across the two sessions suggested an effect of novelty, with
more exploration of open areas in the first session compared to the second. The results indicate
that immobility in the FST may have served as a coping behavior in rats with a model of
depression. Alternatively, the stressors involved in CVS may have failed to induce a model of
depression. The results also reveal a need to create more reliable animal models of depression
and measures of depression-like behavior.
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